Sex Difference in Amebiasis.

Infection with the protozoan parasite Entamoeba histolytica is much more likely to cause severe, focal liver damage in males than females, although the infection rate is the same in both sexes. The differences in disease susceptibility may be due to modulation of key mechanisms of the innate immune response by sex hormones. Complement-mediated mechanisms and estrogen-dependent activated natural killer T cells lead to early elimination of the parasite in females, whereas a pathological immune axis is triggered in males. Testosterone, which is generally thought to have more immunosuppressive properties on cells of the immune response, leads to overwhelming activation of monocytes and host-dependent destruction of liver tissue in males resulting in worse outcomes.

Long-term outcomes and renal responses following autologous hematopoietic stem cell transplantation for light chain deposition disease: a retrospective study on behalf of the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

There is little long-term outcome data on the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in light chain deposition disease (LCDD). We identified 51 LCDD patients in the European Society for Blood and Bone Marrow transplantation registry who had undergone upfront ASCT between 1995 and 2021. The median serum creatinine was 280 µmol/L and 45% required renal replacement therapy (RRT) at time of transplant. The melphalan dose was 100 mg/m2 in 23%, 140 mg/m2 in 55% and 200 mg/m2 in 21%. The rate of very good partial response or better improved from 41% pretransplant to 66% at day +100 post- ASCT. In RRT-independent patients, there was a modest improvement in renal function within the first 3 months; the median estimated glomerular filtration rate increased from 44 to 51 mL/min/1.73 m2. There was no further change between 3 and 12 months post-ASCT. No patient who was RRT-independent at ASCT became RRT dependent by day + 100 post-ASCT. Median follow- up post-ASCT was 84 months (interquartile range [IQR]: 46-122). At 6-years post ASCT, overall survival was 88% (95% confidence interval [CI]: 78-98) and PFS was 44% (95% CI: 28-60). The 2-year cumulative incidence of relapse and non-relapse mortality was 17% (95% CI: 6-27) and 2% (95% CI: 0-6), respectively. The cumulative incidence of renal transplantation at 4 years after ASCT was 27% (95% CI: 13-41) with renal transplantation performed between 6.3 and 52.9 months post-ASCT (median 24.7 months). ASCT represents a feasible option for LCDD patients even if RRT dependent at time of transplant. Outcomes are favorable with low non-relapse mortality and good long-term overall survival.

Neonatal mortality and video assessment of resuscitation in four district hospitals in Pemba, Tanzania.

BACKGROUND: We aimed to assess risk factors for neonatal mortality, quality of neonatal resuscitation (NR) on videos and identify potential areas for improvement. METHODS: This prospective cohort study included women in childbirth and their newborns at four district hospitals in Pemba, Tanzania. Videos were analysed for quality-of-care. Questionnaires on quality-of-care indicators were answered by health workers (HW) and women. Risk factors for neonatal mortality were analysed in a binomial logistic regression model. RESULTS: 1440 newborns were enrolled. 34 newborns died within the neonatal period (23.6 per 1000 live births). Ninety neonatal resuscitations were performed, 20 cases on video. Positive pressure ventilation (PPV) was inadequate in 15 cases (75%). Half (10/20) did not have PPV initiated within the first minute, and in one case (5.0%), no PPV was performed. PPV was not sustained in 16/20 (80%) newborns. Of the 20 videos analysed, death occurred in 10 newborns: 8 after resuscitation attempts and two within the first 24 h. Most of HW 49/56 (87.5%) had received training in NR. CONCLUSIONS: Video analysis of NR revealed significant deviations from guidelines despite 87.5% of HW being trained in NR. Videos provided direct evidence of gaps in the quality of care and areas for future education, particularly effective PPV. IMPACT: Neonatal mortality in Pemba is 23.6 per 1000 livebirths, with more than 90% occurring in the first 24 h of life. Video assessment of neonatal resuscitation revealed deviations from guidelines and can add to understanding challenges and aid intervention design. The present study using video assessment of neonatal resuscitation is the first one performed at secondary-level hospitals where many of the world's births are conducted. Almost 90% of the health workers had received training in neonatal resuscitation, and the paper can aid intervention design by understanding the actual challenges in neonatal resuscitation.

Rescreening on RBANS Delayed Memory Index? Forget About It!

OBJECTIVE: To assess the value of rescreening patients with Alzheimer's disease who do not meet the inclusion criteria for the Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) at the initial assessment. PATIENTS AND METHODS: Participants (aged 50-85 years, without dementia, Mini-Mental State Examination score ≥22, valid Clinical Dementia Rating [CDR] global score, and amyloid status at baseline) were identified in the European Prevention of Alzheimer's Dementia database. Changes from baseline in RBANS DMI were estimated using a mixed model for repeated measurements. Logistic regressions were used to estimate the probability of participants with baseline RBANS DMI 86-95 having RBANS DMI ≤85, CDR global score ≥0.5, and amyloid positivity at 6 and 12 months. RESULTS: There was significant variability in the change in RBANS DMI scores over time (median change at 6 months: 2.0). An estimated 15% of participants with RBANS DMI 86-95 at baseline progressed to ≤85 at 6 months; 8% also achieved CDR global score ≥0.5 and 5% were also amyloid positive. CONCLUSIONS: The results from our analysis indicate that there is limited value in rescreening patients based on their initial RBANS DMI score.

Delirium diagnostic tools in the postoperative setting: A scoping review protocol.

BACKGROUND: Delirium is an acute and fluctuating disturbance in attention, awareness, and cognition, commonly observed in hospital settings, particularly among older adults, critically ill and surgical patients. Delirium poses significant challenges in patient care, leading to increased morbidity, mortality, prolonged hospital stays, and functional decline. AIM: The aim of this review is to map existing evidence on delirium diagnostic tools suitable for use in patients treated surgically due to hip fracture, to inform clinical practice and enhance patient care protocols in the postoperative setting. METHOD: We will conduct a scoping review on delirium diagnostic tools used for adult patients in the postoperative setting according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Eligibility criteria encompass all languages, publications dates, and study designs, with exception of case-reports. We will systematically search multiple databases and include unpublished trials, ensuring a comprehensive review based on a predefined protocol. RESULTS: Results will be presented descriptively, with supplementary tables and graphs. Studies will be grouped by design, surgical specialties, and diagnostic tools to identify potential variations. CONCLUSION: This scoping review will provide an overview of existing delirium diagnostic tools used in the postoperative setting and highlight knowledge-gaps to support future research. Due to the large number of patients affected by postoperative delirium, evidence mapping is much needed to facilitate evidence-based practice.

Significant others in inflammatory arthritis: roles, influences, and challenges-a scoping review.

Improving self-management in individuals with inflammatory arthritis (IA) is crucial for effective disease management. However, current recommendations primarily focus on interventions for the diagnosed individuals, overlooking the potential impact of their significant others on their self-management abilities. This review aims to fill this gap by identifying and mapping relevant research employing both qualitative and quantitative design to provide a broader understanding of the potential of significant others in relation to IA management. We examined studies published from 2007 to 2024 that explore our research questions using electronic databases and grey literature searches. Two independent reviewers meticulously screened and categorized the studies based on a developed framework employing basic content analysis. Out of 20.925 studies, 43 were included: 22 quantitative studies (including 1 educational trial), 20 qualitative studies, and 1 mixed-methods study. Our analysis of the included studies revealed that significant others predominantly provided practical and emotional support and could positively or negatively influence the person with IAs self-management abilities. Additionally, significant others reported their own feelings of emotional distress and expressed the need for knowledge, skills and social support enabling them to provide better support while taking care of them self. Greater focus on the significant others of those diagnosed with IA in their provision of support to this patient group may both improve the people with IA self-management skills and address significant others' reported needs. Future studies should explore the impact of such initiatives through randomized controlled trials.

Sirtuin1, not NAMPT, possesses anti-inflammatory effects in epicardial, pericardial and subcutaneous adipose tissue in patients with CHD.

BACKGROUND: Inflammation in cardiac adipose tissue (AT) is associated with atherosclerosis. We investigated whether the epicardial-, pericardial and pre-sternal subcutaneous AT (EAT, PAT and SAT) expression of Sirtuin1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) are involved in the inflammatory process in coronary heart disease (CHD), and potentially associated to nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related markers, macrophage polarization markers, cell markers and the cardiometabolic profile. METHODS: In this cohort study performed between 2016 and 2018, EAT, PAT and SAT biopsies were retrieved from 52 CHD patients (77% men, median age 67) undergoing open-chest coronary artery bypass grafting (CABG), and 22 patients (50% men, median age 69) undergoing aortic valve replacement serving as controls. AT samples were snap-frozen at - 80 °C until RNA extraction and AT expression of actual markers, relatively quantified by PCR. Circulating SIRT1 and NAMPT were measured with Enzyme-linked immunosorbent assays (ELISAs). Non-parametric statistical tests were mainly used, including Friedman's test coupled to Wilcoxon signed-rank test and Spearman Correlation. RESULTS: SIRT1 and NAMPT levels were similar in CHD and controls. In CHD, SIRT1 and NAMPT were inter-correlated in all AT compartments (r = 0.37-0.56, p < 0.01, all), and differently expressed between compartments, with the highest expression in SAT, significantly different from EAT (p < 0.01, both). Circulating SIRT1 and NAMPT levels were inversely associated (r = - 0.32, p = 0.024). In EAT and SAT, SIRT1 expression was inversely associated with IL-18 (r = - 0.43 and r = - 0.38, p < 0.01, both), whereas NAMPT expression was positively associated with the NLRP3 inflammasome-related markers in all compartments (r = 0.37-0.55, p < 0.01, all). While SIRT1 and NAMPT correlated to nitric oxide synthase 2 (NOS2), especially in SAT (r = 0.50-0.52, p ≤ 0.01, both), SIRT1 expression was related to endothelial cells, and NAMPT to macrophages. SIRT1 levels were correlated to weight and waist (r = 0.32 and r = 0.38, p < 0.03, both) and inversely to triglycerides and glycated haemoglobin (HbA1c) (r = - 0.33-- 0.37, p < 0.03, all), the latter positively correlated to NAMPT concentration (r = 0.39, p = 0.010). CONCLUSION: The study indicates that targeting SIRT1, with its anti-inflammatory properties, may be a novel anti-inflammatory strategy in preventing atherosclerosis and CHD progression. NAMPT may be an early player in AT inflammation, mediating/reflecting a pro-inflammatory state. TRIAL REGISTRATION: Registration: Clinicaltrials.gov ID: NCT02760914, registered the 5th of February 2016, http://clinicaltrials.gov/NCT02760914.

Risk factors of stillbirths in four district hospitals on Pemba Island, Tanzania: a prospective cohort study.

BACKGROUND: More than 2 million third-trimester stillbirths occur yearly, most of them in low- and middle-income countries. Data on stillbirths in these countries are rarely collected systematically. This study investigated the stillbirth rate and risk factors associated with stillbirth in four district hospitals in Pemba Island, Tanzania. METHODS: A prospective cohort study was completed between the 13th of September and the 29th of November 2019. All singleton births were eligible for inclusion. Events and history during pregnancy and indicators for adherence to guidelines were analysed in a logistic regression model that identified odds ratios [OR] with a 95% confidence interval [95% CI]. RESULTS: A stillbirth rate of 22 per 1000 total births in the cohort was identified; 35.5% were intrapartum stillbirths (total number of stillbirths in the cohort, n = 31). Risk factors for stillbirth were breech or cephalic malpresentation (OR 17.67, CI 7.5-41.64), decreased or no foetal movements (OR 2.6, CI 1.13-5.98), caesarean section [CS] (OR 5.19, CI 2.32-11.62), previous CS (OR 2.63, CI 1.05-6.59), preeclampsia (OR 21.54, CI 5.28-87.8), premature rupture of membranes or rupture of membranes 18 h before birth (OR 2.5, CI 1.06-5.94) and meconium stained amniotic fluid (OR 12.03, CI 5.23-27.67). Blood pressure was not routinely measured, and 25% of women with stillbirths with no registered foetal heart rate [FHR] at admission underwent CS. CONCLUSIONS: The stillbirth rate in this cohort was 22 per 1000 total births and did not fulfil the Every Newborn Action Plan's goal of 12 stillbirths per 1000 total births in 2030. Awareness of risk factors associated with stillbirth, preventive interventions and improved adherence to clinical guidelines during labour, and hence improved quality of care, are needed to decrease the stillbirth rate in resource-limited settings.

HIF-1α modulates sex-specific Th17/Treg responses during hepatic amoebiasis.

BACKGROUND & AIMS: An invasive form of intestinal Entamoeba (E.) histolytica infection, which causes amoebic liver abscess, is more common in men than in women. Immunopathological mechanisms are responsible for the more severe outcome in males. Here, we used a mouse model of hepatic amoebiasis to investigate the contribution of hepatic hypoxia-inducible factor (HIF)-1α to T helper 17 (Th17)/regulatory T cell (Treg) responses in the context of the sex-specific outcome of liver damage. METHODS: C57BL/6J mice were infected intrahepatically with E. histolytica trophozoites. HIF-1α expression was determined by qPCR, flow cytometry and immunohistochemistry. Tregs and Th17 cells were analysed by immunohistochemistry and flow cytometry. Finally, male and female hepatocyte-specific Hif1α knockout mice were generated, and the effect of HIF-1α on abscess development, the cytokine milieu, and Th17/Treg differentiation was examined. RESULTS: E. histolytica infection increased hepatic HIF-1α levels, along with the elevated frequencies of hepatic Th17 and Treg cells. While the Th17 cell population was larger in male mice, Tregs characterised by increased expression of Foxp3 in female mice. Male mice displayed increased IL-6 expression, contributing to immunopathology; this increase in IL-6 expression declined upon deletion of hepatic HIF-1α. In both sexes, hepatic deletion of HIF-1α reduced the Th17 cell frequency; however, the percentage of Tregs was reduced in female mice only. CONCLUSIONS: Hepatic HIF-1α modulates the sex-specific outcome of murine E. histolytica infection. Our results suggest that in male mice, Th17 cells can be modulated by hepatic HIF-1α via IL-6, indicating marked involvement in the immunopathology underlying abscess development. Strong expression of Foxp3 by hepatic Tregs from female mice suggests a potent immunosuppressive function, leading to initiation of liver regeneration. LAY SUMMARY: Infection with the parasite Entamoeba histolytica activates immunopathological mechanisms in male mice, which lead to liver abscesses that are larger than those in female mice. In the absence of the protein HIF-1α in hepatocytes, abscess formation is reduced; moreover, the sex difference in abscess size is abolished. These results suggest that HIF-1α modulates the immune response involved in the induction of immunopathology, resulting in differential disease susceptibility in males and females.

The effect of household crowding and composition on health in an Inuit cohort in Greenland.

Aims: This study aims to investigate the association between household crowding and household composition and self-rated health and mental health (GHQ scale) among the Inuit in Greenland. Poor housing conditions are a concern in Greenland, especially in the villages, where socioeconomic standards in general are lower. Methods: A cohort of 1282 adults participated in two population-based surveys in Greenland, the Inuit Health in Transition survey 2005-2010 (baseline) and The Health Survey in Greenland 2014 (follow-up). Associations between household conditions at baseline and health outcomes at follow-up (poor self-rated health and mental health measured by the GHQ scale) were examined using logistic regression models, adjusting for covariates at baseline. Results: Participants living in an overcrowded dwelling (more than one person per room) at baseline were more likely to report poor self-rated health at follow-up (OR 1.47; 95% CI 1.09; 1.99) compared with those not living in an overcrowded dwelling. In addition, participants who lived alone at baseline were more likely (OR 1.98; 95% CI 1.09; 3.58) to experience poor mental health at follow-up compared with those who lived with children. Conclusions: Results indicate that household conditions are related to health in Greenland. Public health authorities should work to ensure affordable housing of good quality in all communities.

Classification of Amyloidosis by Model-Assisted Mass Spectrometry-Based Proteomics.

Amyloidosis is a rare disease caused by the misfolding and extracellular aggregation of proteins as insoluble fibrillary deposits localized either in specific organs or systemically throughout the body. The organ targeted and the disease progression and outcome is highly dependent on the specific fibril-forming protein, and its accurate identification is essential to the choice of treatment. Mass spectrometry-based proteomics has become the method of choice for the identification of the amyloidogenic protein. Regrettably, this identification relies on manual and subjective interpretation of mass spectrometry data by an expert, which is undesirable and may bias diagnosis. To circumvent this, we developed a statistical model-assisted method for the unbiased identification of amyloid-containing biopsies and amyloidosis subtyping. Based on data from mass spectrometric analysis of amyloid-containing biopsies and corresponding controls. A Boruta method applied on a random forest classifier was applied to proteomics data obtained from the mass spectrometric analysis of 75 laser dissected Congo Red positive amyloid-containing biopsies and 78 Congo Red negative biopsies to identify novel "amyloid signature" proteins that included clusterin, fibulin-1, vitronectin complement component C9 and also three collagen proteins, as well as the well-known amyloid signature proteins apolipoprotein E, apolipoprotein A4, and serum amyloid P. A SVM learning algorithm were trained on the mass spectrometry data from the analysis of the 75 amyloid-containing biopsies and 78 amyloid-negative control biopsies. The trained algorithm performed superior in the discrimination of amyloid-containing biopsies from controls, with an accuracy of 1.0 when applied to a blinded mass spectrometry validation data set of 103 prospectively collected amyloid-containing biopsies. Moreover, our method successfully classified amyloidosis patients according to the subtype in 102 out of 103 blinded cases. Collectively, our model-assisted approach identified novel amyloid-associated proteins and demonstrated the use of mass spectrometry-based data in clinical diagnostics of disease by the unbiased and reliable model-assisted classification of amyloid deposits and of the specific amyloid subtype.

Combined Subcutaneous Fat Aspirate and Skin Tru-Cut Biopsy for Amyloid Screening in Patients with Suspected Systemic Amyloidosis.

Screening for systemic amyloidosis is typically carried out with abdominal fat aspirates with varying reported sensitivities. Fat aspirates are preferred for use in primary screening instead of organ biopsies as they are less invasive and thereby minimize the potential risk of complications. At Odense Amyloidosis Center, we performed a prospective study on whether the combined use of fat aspirate and tru-cut skin biopsy could increase the diagnostic sensitivity. Both fat aspirates and skin biopsies were screened with Congo Red staining, and positive biopsies were subsequently subtyped using immunoelectron microscopy and mass spectrometry. Seventy-six patients were included. In total, 24 patients had systemic amyloidosis (11 AL, 12 wtATTR, 1 AA), and 6 patients had localized amyloidosis. Combined fat aspirate and skin biopsy were Congo Red-positive in 15 patients (overall sensitivity (OS) 62.5%). Fat aspirates were positive in 14 patients (OS 58.3%), and the skin biopsy was positive in 5 patients (OS 20.8%). In only one patient did the skin biopsy add extra diagnostic information. The sensitivity differed between AL and ATTR amyloidosis-81.8% and 41.7%, respectively. Using skin biopsy as the only screening method is not recommended.

Long-Term Survival, Health, Social Functioning, and Education in Patients With an Enterovirus Central Nervous System Infection, Denmark, 1997-2016.

BACKGROUND: The long-term clinical course of patients with an enterovirus central nervous system infection (ECI) is poorly understood. METHODS: We performed a nationwide population-based cohort study of all Danish patients with ECI diagnosed 1997-2016 (n = 1745) and a comparison cohort from the general population individually matched on date of birth and sex (n = 17 450). Outcomes were categorized into mortality and risk of cancer and likely measures of neurological sequelae: neuropsychiatric morbidities, educational landmarks, use of hospital services, employment, receipt of disability pension, income, number of sick leave days, and nursing home residency. RESULTS: Mortality in the first year was higher among patients with ECI (mortality rate ratio [MRR] = 10.0; 95% confidence interval [CI], 4.17-24.1), but thereafter mortality was not higher (MMR = 0.94; 95% CI, 0.47-1.86). Long-term outcomes for patients with ECI were not inferior to those of the comparison cohort for risk of cancer, epilepsy, mental and behavioral disorders, dementia, depression, school start, school marks, high school education, use of hospital services, employment, receipt of disability pension, income, days of sick leave, or nursing home residency. CONCLUSIONS: Diagnosis of an ECI had no substantial impact on long-term survival, health, or social/educational functioning.

Clinically-suspected cast nephropathy: A retrospective, national, real-world study.

Presentation with severe acute kidney injury due to cast nephropathy (CN) is a medical emergency in multiple myeloma (MM), with high risk of dialysis-dependent renal failure and death. Accrual of patients with CN into interventional studies is difficult, while phase III trials exclude patients with severe renal insufficiency. Real-world data are warranted. We assessed 2252 patients from the population-based Danish Multiple Myeloma Registry (DMMR) who were diagnosed between 2013 and 2017. We identified 204 patients with clinically-suspected CN, defined as serum creatinine concentration >177 µmol/L and serum free light chain (sFLC) concentration >1000 mg/L at the time of diagnosis. The median age was 72 years. Thirty-one percent of patients presented with dialysis-dependent renal failure. Kidney biopsies were performed in 19% of patients and showed CN in 74% of cases. Despite prompt initiation of bortezomib-based therapy in 94% of patients, 33% of patients died in the first year after diagnosis. Compared with the rest of the patients in the DMMR with symptomatic MM, patients with clinically-suspected CN had worse overall survival (OS) irrespective of transplant eligibility. Achievement of renal recovery was associated with deep reductions of involved sFLC. Achievement of very good partial response or better in the first line of therapy and/or deep reduction of involved sFLC at 3 months after initiation of therapy were associated with superior OS. In conclusion, MM patients presenting with clinically-suspected CN have an alarmingly high one-year mortality when treated with current standards of care. Early and deep hematologic response is crucial for survival.

Lower rates of hypoglycaemia in older individuals with type 2 diabetes using insulin degludec versus insulin glargine U100: Results from SWITCH 2.

AIM: This study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial). METHODS: In this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double-blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose-confirmed (plasma glucose <56 mg/dL; 3.1 mmol/L) symptomatic hypoglycaemia events during the two 16-week maintenance periods. RESULTS: For individuals ≤65 (n = 450) and >65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1-40) vs 15 (1-54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m2 , respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient-year for individuals ≤65 years and were 3.5 and 4.1 events/patient-year for individuals >65 years with degludec and glargine U100, respectively. CONCLUSION: Treatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D.

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7).

AIMS: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. MATERIALS AND METHODS: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs). RESULTS: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes. CONCLUSIONS: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age.

Long-Term Survival after Invasive or Conservative Strategy in Elderly Patients with non-ST-Elevation Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: The optimal management of elderly patients with non-ST-segment elevation myocardial infarction (NSTEMI) is still discussed. We aimed to study short- and long-term survival in NSTEMI patients ≥75 years managed with an invasive or a conservative strategy. METHODS: NSTEMI patients admitted to Oslo University Hospital Ulleval during 2005-2011 were included consecutively in a prospective registry. Vital status until December 31, 2013, was obtained from the Norwegian Cause of Death Registry. Patients ≥75 years were identified, and 30-day and 7-year survival were analyzed. Logistic- and Cox regression was used to estimate OR and hazard ratio (HR) for death in the invasive versus conservative group, adjusting for registered confounders. RESULTS: There were 2,064 NSTEMI patients ≥75 years (48.2% women); 1,200 (58.1%) were treated with an invasive strategy, and were younger, more likely to be male and previously revascularized compared to 864 (41.9%) patients treated conservatively (p < 0.0001 for all). Survival at 30-day was 94.9% in the invasive and 76.6% in the conservative group. For 30-day survivors, 7-year survival was 47.4% (95% CI 42.9-51.8) and 11.6% (95% CI 8.3-15.6), respectively. After multivariate adjustment, an invasive strategy was associated with lower long-term risk (adjusted HR [aHR] 0.49 [95% CI 0.41-0.59]). Actual revascularization was associated with lower risk of long-term mortality compared to angiography only (aHRPCI 0.73 [95% CI 0.59-0.90], aHRCABG 0.43 [95% CI 0.28-0.65]). CONCLUSION: In this real-life cohort of NSTEMI patients ≥75 years, 30-day survival was 95%, and 7-year survival was 47% with an invasive strategy. Revascularized patients had a superior long-term prognosis. With a conservative strategy, short- and long-term survival was lower, probably due to selection bias and unmeasured confounding.

Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised, crossover trial.

AIMS/HYPOTHESIS: The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus. METHODS: In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8 ± 0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l ± 10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H215O-positron emission tomographies (PET) per session. RESULTS: Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] -0.63 [95% CI -1.13, -0.14], p = 0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p = 0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p < 0.05). Working memory activation (mDSST - cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p = 0.002). CONCLUSIONS/INTERPRETATION: During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion. TRIAL REGISTRATION: NCT01789593, clinicaltrials.gov FUNDING: This study was funded by Novo Nordisk.

Insulin Degludec 200 Units/mL Is Associated With Lower Injection Frequency and Improved Patient-Reported Outcomes Compared With Insulin Glargine 100 Units/mL in Patients With Type 2 Diabetes Requiring High-Dose Insulin.

IN BRIEF Many patients with type 2 diabetes require high basal insulin doses, necessitating multiple injections, increasing patient burden, and resulting in reduced treatment adherence. This randomized, controlled, crossover trial compared the efficacy, safety, and patient-reported outcomes for a concentrated formulation of insulin degludec (200 units/mL) to those of insulin glargine in patients requiring high doses of basal insulin. By offering equivalent glycemic control while reducing the rate of confirmed hypoglycemia and the number of injections required for administration, insulin degludec 200 units/mL may be preferred by patients with type 2 diabetes who require high basal insulin doses.

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial.

IMPORTANCE: Hypoglycemia, common in patients with type 1 diabetes, is a major barrier to achieving good glycemic control. Severe hypoglycemia can lead to coma or death. OBJECTIVE: To determine whether insulin degludec is noninferior or superior to insulin glargine U100 in reducing the rate of symptomatic hypoglycemic episodes. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, crossover noninferiority trial involving 501 adults with at least 1 hypoglycemia risk factor treated at 84 US and 6 Polish centers (January 2014-January 12, 2016) for two 32-week treatment periods, each with a 16-week titration and a 16-week maintenance period. INTERVENTIONS: Patients were randomized 1:1 to receive once-daily insulin degludec followed by insulin glargine U100 (n = 249) or to receive insulin glargine U100 followed by insulin degludec (n = 252) and randomized 1:1 to morning or evening dosing within each treatment sequence. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of overall severe or blood glucose-confirmed (<56 mg/dL) symptomatic hypoglycemic episodes during the maintenance period. Secondary end points included the rate of nocturnal symptomatic hypoglycemic episodes and proportion of patients with severe hypoglycemia during the maintenance period. The noninferiority criterion for the primary end point and for the secondary end point of nocturnal hypoglycemia was defined as an upper limit of the 2-sided 95% CI for a rate ratio of 1.10 or lower; if noninferiority was established, 2-sided statistical testing for superiority was conducted. RESULTS: Of the 501 patients randomized (mean age, 45.9 years; 53.7% men), 395 (78.8%) completed the trial. During the maintenance period, the rates of overall symptomatic hypoglycemia were 2200.9 episodes per 100 person-years' exposure (PYE) in the insulin degludec group vs 2462.7 episodes per 100 PYE in the insulin glargine U100 group for a rate ratio (RR) of 0.89 (95% CI, 0.85-0.94; P < .001 for noninferiority; P < .001 for superiority; rate difference, -130.31 episodes per 100 PYE; 95% CI, -193.5 to -67.16). The rates of nocturnal symptomatic hypoglycemia were 277.1 per 100 PYE in the insulin degludec group vs 428.6 episodes per 100 PYE in the insulin glargine U100 group, for an RR of 0.64 (95% CI, 0.56-0.73; P < .001 for noninferiority; P < .001 for superiority; rate difference, -61.94 episodes per 100 PYE; 95% CI, -83.85 to -40.03). A lower proportion of patients in the insulin degludec than in the insulin glargine U100 group experienced severe hypoglycemia during the maintenance period (10.3%, 95% CI, 7.3%-13.3% vs 17.1%, 95% CI, 13.4%-20.8%, respectively; McNemar P = .002; risk difference, -6.8%; 95% CI, -10.8% to -2.7%). CONCLUSIONS AND RELEVANCE: Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, 32 weeks' treatment with insulin degludec vs insulin glargine U100 resulted in a reduced rate of overall symptomatic hypoglycemic episodes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02034513.